Disulfiram (DSF), also known as Antabuse, is a Food and Drug Administration (FDA)-approved drug, which has been used for anti-alcoholism in clinic for more than 60 years (1). DSF is a member of the dithiocarbamate (DTC) family, which comprises a broad class of molecules possessing an R1R2NC (S) SR3 functional group that gives the family the ability to complex metals and react with sulfhydryl groups. DSF was originally found to act as an irreversible inhibitor of aldehyde dehydrogenase (ALDH) for anti-alcoholism and is safe with no toxicity (2). Due to the discovery that DSF and its metabolites kill cancer cells and slow tumor growth in animal models (3, 4) and human patients (3, 5), there has been an effort for repurposing this drug for cancer treatment (6–9). Several potential targets of DSF’s action, such as ALDH, NF-κB and proteasome, etc., were recently found (please see references therein)(10). It appears that DSF can act against a broad spectrum of malignancies, and, it can also target cancer cells with cancer stem cell-like properties. It has been known that the tumor cytotoxic activity of DSF is copper-dependent. The precise mechanisms of DSF’s anticancer activity, however, are still unknown. A recent work by Skrott et al. identified valosin-containing protein (VCP)/p97 segregase adaptor NLP4 as new molecular target of DSF (11), providing a new rationale for clinical trials aiming at repurposing this old drug.

NPL4 is one of major substrate adaptors of VCP/p97 segregase, which is conserved from yeast to human. The hexameric structure with AAA-type ATPase activity (Figure 1), together with adaptors/cofactors capable of binding to ubiquitinated substrates, enables VCP/p97 segregase to impose conformational changes on substrate proteins, and, to pull the ubiquitinated proteins out of membranes, segregate them from their binding partners or